It has been established that most of the beneficial effects of transplanted cells are indirect: injected cells secrete paracrine factors that promote endogenous heart repair. Among those secreted substances, exosomes are 30-100 nm vesicles secreted by a wide range of cell types including tumor cells and stem cells. Exosomes can transport microRNAs (miRs) that enable cells to communicate with neighboring cells to change their behavior. The essential miR cargos underlying the therapeutic potencies of exosomes have yet to be determined. In addition, unlike stem cells, exosomes do not have migratory ability therefore local injections are performed to ensure delivery. However, direction injection into the heart is not trivial, normally requiring open- chest surgery or sophisticated endomyocardial injection setups such as the NOGA mapping system. It is crucial to develop techniques to target systemically delivered exosomes to the heart injury. Our long-term goal is to create exosomes with optimized cargos and surfaces for precision cardiac repair. In our preliminary studies, we compared cultured cardiac stromal cells from normal and failing human hearts, and isolated exosomes from these cells. In vitro experiments and animal studies indicate an impaired regenerative activity of exosomes from heart failure patients. In addition, miR array revealed dysregulation of miR-21 in heart failure exosomes. Based on those preliminary results, we hypothesize that: i) there is a loss of therapeutic properties in exosomes from heart failure and such functional loss is due to alterations in repertoire miRs such as miR-21; ii) modulating such miR cargos could rescue the regenerative potential of the diseased exosomes; iii) efficient systemic delivery and injury targeting can be achieved by exosomal surface modification. Studies proposed in this proposal are highly significant since they aim to enhance our fundamental understating of mechanisms underlying exosomes' reparative function but may also pave the way for future clinical translation.